Trimethyl phosphate

Endpoint summary

Description of key information

Trimethyl Phosphate (molecular weight of 140,07 g/mol) is a colorless liquid, which is highly soluble in water (measured water solubility: 5000 g/l at 25 °C (Aqueous Solubility Data, Handbook of Aqueous Solubility Data, 2003, Samuel H. Yalkowsky; Yan He; see chapter 4.8 water solubility).The measured log Pow is -0.46 at 25 °C (Microbial Degradation Study of Trimethyl phosphate, Chemicals Inspection & Testing Institute, Japan (CITI), Chemical Goods Safety Center, Kyushu Laboratory, 1984, see chapter 4.7 partition coefficient), indicating a possible general absorption of Trimethyl Phosphate.

Absorption

 

In an acute oral toxicity study, rats were administered to Trimethyl Phosphate which showed an LD50 value of 840 mg/kg bw (OECD SIDS Report - Trimethyl Phosphate, UNEP PUBLICATIONS, 1996, see chapter 7.2.1 acute oral toxicity). Therefore, bioavailability of Trimethyl Phosphate after oral administration is indicated.

In an acute dermal toxicity study with New Zealand White rabbits the LD50 was determined to be 3388 mg/kg Trimethyl Phosphate (Range-Finding toxicity data: List VII, Am. Ind. Hyg. Assoc. J., 1969, 30:5, 470-476, see chapter 7.2.3 acute dermal toxicity). Due to the experimental acute oral and the lower dermal toxicity, it appears that Trimethyl Phosphate is absorbed more rapidly through gastrointestinal tract than skin.

Most organophosphate compounds are absorbed from skin, conjunctiva, gastrointestinal tract & lung. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 1071]

Trimethylphosphate is absorbed rapidly and completely through all absorption pathways. [Jackson, H., A. R. Jones: Nature (Lond.) 220, 591 (1968); Jones, A. R.: Experientia (Basel) 26, 492 (1970)].

 

Metabolism:

 

In a combined repeated dose and reproductive/developmental screnning test rats showed progressive paralytic gait and decreased motor activity as well as significantly lower body weight gain of males and females given 250 mg/kg than those of the controls. Significant decreased erythrocyte counts, hemoglobin concentration, hematocrit and A/G ratio, and increased platelet counts, percent of segmented neutrophile, cholinesterase activity, total cholesterol and calcium levels were noted in the males when >=100 mg/kg Trimethyl phosphate were administered. At terminal necropsy, compound-related alterations in organ weights included:

1. significant increases in the kidney weight in the males when 40 and 100 mg/kg

Trimethyl phosphate were administered

2. significant increases in

the thymus weight

in the males when

100 mg/kg and in the females when 40 mg/kg were administered

and 3. a significant decrease in the epididymal weight in the males when >=100 mg/kg Trimethyl phosphate were administered.

In the histopathological examinations, major lesions noted in males and females given >= 100 mg/kg Trimethyl phosphate included nephropathy characterized by tubular and papillary alteration such as increased eosinophilic droplets in tubular epithelium, increased regeneration of tubules and papillary necrosis, atrophy of the thymus, liver and testis, increased atretic follicles in the ovary (250 mg/kg female only), and degeneration of nerve fiver in the spinal cord or the peripheral nerves (e.g., sciatic nerve). The incidence and severity of these lesions increased with dose and were greater in males than females. (Yutaka Hashimoto, Hatano Research Institute, Food and Drug Safety Center, Japan, 1994)

Rats treated orally at 100 mg/kg and mice treated ip at 1000 mg/kg with (32)P-labeled trimethyl phosphate excreted primarily dimethyl phosphate in the urine. Only traces of the parent compound were detected, and only in the rats at less than 6 hr after treatment. S-Methyl cysteine and S-methyl cysteine N-acetate were also isolated. Small amounts of S-methyl glutathione were detected, presumably the initial methylation product in this series of metabolites.

Metabolism of trimethyl phosphate was faster in the mouse than in the rat, but there was no evidence of further conversion to monomethyl phosphate in either species. [Snyder, R. (ed.). Ethel Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 482]

Both rat liver and rat intestinal tissue degrade TMP, but not the kidney.

TMP is degraded to dimethyl phosphate (DMP), not to monoalkyl phosphate or even to free phosphoric acid.

The general pathway is:

TMP ----> DMP and S-Methylglutathion ----> S-Methylcystein ----> S-Methylcystein-N-acetat

TMP reacts almost quantitatively with glutathione in vitro. Both S-methylglutathione and dimethylphosphate are found on reaction with liver homogenate.

Mouse and rat metabolise TMP relatively quickly after oral, less quickly after intraperitoneal administration; Here almost 90% is metabolised in 16 hours, almost everything is metabolised in 96 hours. [Jackson, H., A. R. Jones: Nature (Lond.) 220, 591 (1968); Jones, A. R.: Experientia (Basel) 26, 492 (1970)]

Excretion:

The metabolites are predominantly secreted with the urine [Jackson, H., A. R. Jones: Nature (Lond.) 220, 591 (1968); Jones, A. R.: Experientia (Basel) 26, 492 (1970)].

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential